U.S. patent application number 15/925555 was filed with the patent office on 2018-10-04 for method for oxygenative coupling of alkynes using acid catalyst.
The applicant listed for this patent is INDUSTRY-UNIVERSITY COOPERATION FOUNDATION HANYANG UNIVERSITY. Invention is credited to Patil DILIP, Seung Woo KIM, Huong Quynh NGUYEN, Seung Hoon SHIN.
Application Number | 20180282273 15/925555 |
Document ID | / |
Family ID | 63672940 |
Filed Date | 2018-10-04 |
United States Patent
Application |
20180282273 |
Kind Code |
A1 |
SHIN; Seung Hoon ; et
al. |
October 4, 2018 |
METHOD FOR OXYGENATIVE COUPLING OF ALKYNES USING ACID CATALYST
Abstract
The present disclosure relates to a method for preparing various
physiologically active pharmaceutical ingredients, such as a
1,1-diaryl compound and a 1,1-diheteroaryl compound (specifically,
a 1,1-diaryl carbonyl compound), in an economical and convenient
manner under mild conditions without using an expensive transition
metal catalyst by activating an alkyne compound (e.g., an ynamide)
using a Bronsted acid as a catalyst to induce a reaction of the
activated alkyne compound and a N--O bond oxidant to form an adduct
intermediate and then inducing a coupling reaction of the adduct
intermediate with various nucleophilic organic compounds (e.g., a
nucleophilic arene compound).
Inventors: |
SHIN; Seung Hoon; (Seoul,
KR) ; DILIP; Patil; (Seoul, KR) ; KIM; Seung
Woo; (Seoul, KR) ; NGUYEN; Huong Quynh;
(Seoul, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INDUSTRY-UNIVERSITY COOPERATION FOUNDATION HANYANG
UNIVERSITY |
Seoul |
|
KR |
|
|
Family ID: |
63672940 |
Appl. No.: |
15/925555 |
Filed: |
March 19, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 231/10 20130101;
C07D 209/24 20130101; C07C 213/08 20130101; C07C 231/14 20130101;
C07C 231/14 20130101; C07C 235/78 20130101 |
International
Class: |
C07D 209/24 20060101
C07D209/24; C07C 231/10 20060101 C07C231/10; C07C 213/08 20060101
C07C213/08 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 20, 2017 |
KR |
10-2017-0034372 |
Claims
1. A method for preparing an alkyne compound-derived reactive
intermediate, the method comprising: reacting an alkyne compound
represented by General Formula 1 with a N--O bond oxidant in the
presence of a Bronsted acid-containing catalyst in an organic
solvent to form an alkyne-oxidant adduct: ##STR00028## wherein,
R.sup.1 is carbonyl (R.sup.4C(O)), sulfonyl (R.sup.4SO.sub.2),
carbamate (R.sup.4OC(O)), or sulfinyl (R.sup.4S(O)), as a
substituent that lowers electron density of N atoms, and R.sup.4 is
selected from the group consisting of a C1-C40 alkyl group, a
C2-C40 alkenyl group, a C2-C40 alkynyl group, a C6-C40 aryl group,
a heteroaryl group having 5 to 40 heteronuclear atoms, a C6-C40
aryloxy group, a C1-C40 alkyloxy group, a C6-C40 arylamine group, a
C1-C40 alkylamine group, a C1-C40 alkyl group having C6-C40 aryl, a
C1-C40 alkyl group having 1 to 6 alcohol groups, a C1-C40 alkyl
group having C1-C40 amine, a C3-C40 cycloalkyl group, and a
heterocycloalkyl group having 3 to 40 heteronuclear atoms; R.sup.2
and R.sup.3 each are independently selected from the group
consisting of hydrogen, deuterium, halogen, a cyano group, a C1-C40
alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group, a
C6-C40 aryl group, a heteroaryl group having 5 to 40 heteronuclear
atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy group, a C6-C40
arylamine group, a C1-C40 alkylamine group, a C1-C40 alkyl group
having C6-C40 aryl, a C1-C40 alkyl group having 1 to 6 alcohol
groups, a C1-C40 alkyl group having C1-C40 amine, a C3-C40
cycloalkyl group, and a heterocycloalkyl group having 3 to 40
heteronuclear atoms, and R.sup.2 and R.sup.3 may bind to a
neighboring group to form a fused ring; and R.sup.1 and R.sup.2 may
bind to each other to form an indole ring, and respective
substituents at positions 2, 3, 4, 5, 6, and 7 of the indole are
selected from the group consisting of a C1-C40 alkyl group, a
C2-C40 alkenyl group, a C2-C40 alkynyl group, a C6-C40 aryl group,
a heteroaryl group having 5 to 40 heteronuclear atoms, a C6-C40
aryloxy group, a C1-C40 alkyloxy group, a C6-C40 arylamine group, a
C1-C40 alkylamine group, a C1-C40 alkyl group having C6-C40 aryl, a
C1-C40 alkyl group having 1 to 6 alcohol groups, a C1-C40 alkyl
group having C1-C40 amine, a C3-C40 cycloalkyl group, and a
heterocycloalkyl group having 3 to 40 heteronuclear atoms.
2. A method for oxygenative coupling of an alkyne compound, the
method comprising: reacting an alkyne compound represented by
General Formula 1 with a N--O bond oxidant in the presence of a
Bronsted acid-containing catalyst in an organic solvent to form an
alkyne-oxidant adduct intermediate; and subsequently reacting the
alkyne-oxidant adduct intermediate with a nucleophile (Nu) to form
a compound represented by General Formula 2 below: ##STR00029##
wherein, R.sup.1 is carbonyl (R.sup.4C(O)), sulfonyl
(R.sup.4SO.sub.2), carbamate (R.sup.4OC(O)), or sulfinyl
(R.sup.4S(O)), as a substituent that lowers electron density of N
atoms, and R.sup.4 is selected from the group consisting of a
C1-C40 alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group,
a C6-C40 aryl group, a heteroaryl group having 5 to 40
heteronuclear atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy
group, a C6-C40 arylamine group, a C1-C40 alkylamine group, a
C1-C40 alkyl group having C6-C40 aryl, a C1-C40 alkyl group having
1 to 6 alcohol groups, a C1-C40 alkyl group having C1-C40 amine, a
C3-C40 cycloalkyl group, and a heterocycloalkyl group having 3 to
40 heteronuclear atoms; R.sup.2 and R.sup.3 each are independently
selected from the group consisting of hydrogen, deuterium, halogen,
a cyano group, a C1-C40 alkyl group, a C2-C40 alkenyl group, a
C2-C40 alkynyl group, a C6-C40 aryl group, a heteroaryl group
having 5 to 40 heteronuclear atoms, a C6-C40 aryloxy group, a
C1-C40 alkyloxy group, a C6-C40 arylamine group, a C1-C40
alkylamine group, a C1-C40 alkyl group having C6-C40 aryl, a C1-C40
alkyl group having 1 to 6 alcohol groups, a C1-C40 alkyl group
having C1-C40 amine, a C3-C40 cycloalkyl group, and a
heterocycloalkyl group having 3 to 40 heteronuclear atoms, and
R.sup.2 and R.sup.3 may bind to a neighboring group to form a fused
ring; R.sup.1 and R.sup.2 may bind to each other to form an indole
ring, and respective substituents at positions 2, 3, 4, 5, 6, and 7
of the indole are selected from the group consisting of a C1-C40
alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group, a
C6-C40 aryl group, a heteroaryl group having 5 to 40 heteronuclear
atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy group, a C6-C40
arylamine group, a C1-C40 alkylamine group, a C1-C40 alkyl group
having C6-C40 aryl, a C1-C40 alkyl group having 1 to 6 alcohol
groups, a C1-C40 alkyl group having C1-C40 amine, a C3-C40
cycloalkyl group, and a heterocycloalkyl group having 3 to 40
heteronuclear atoms; and Nu is selected from the group consisting
of a C6-C40 substituted phenol group, a C6-C40 substituted aniline
group, an indole group having 8 to 40 heteronuclear atoms, a
pyrrole group having 5 to 40 heteronuclear atoms, a 1,2-diazole
group having 5 to 40 heteronuclear atoms, a C3-C40 silyl enol ether
group, and a C3-C40 terminal vinyl group.
3. The method of claim 2, wherein the N--O bond oxidant is
represented by General Formula 3 or 4 below: ##STR00030## wherein
R, R', and R'' each are a C1-C40 heteroaryl compound that forms a
ring together with N, and may also be a compound having axial
chirality in which the rotation of a R'-R'' bond is restricted
according to the substituent.
4. The method of claim 3, wherein the N--O bond oxidant has
chirality.
5. The method of claim 4, wherein the N--O bond oxidant has an S
confirmation represented by Chemical Formula 1 below:
##STR00031##
6. The method of claim 2, wherein the N--O bond oxidant is
represented by General Formula 5 below: ##STR00032## wherein R'''
is hydrogen, a halogen, a dihalogen, a cyano group, an alkoxy
group, or a nitro group.
7. The method of claim 6, wherein R''' is hydrogen, 2-chloro,
2-bromo, 2-methoxy, 4-nitro, 2,4-dichloro, 2,6-dichloro,
2,6-dibromo or 3,5-dibromo.
8. The method of claim 2, wherein the oxygenative coupling is
performed through a single stage.
9. The method of claim 2, wherein the Bronsted acid exhibits
acidity with an acid dissociation constant (pKa) in the range of
-10 to 7 in an aqueous solution.
10. The method of claim 9, wherein the Bronsted acid is selected,
according to the structure of a counter anion, from the group
consisting of (i) conjugate acids of sulfonate, bis-sulfonimide,
phosphate, phosphoramide, or carboxylate, for oxygen acids and
nitrogen acids; (ii) conjugate acids of carbanions with aryl groups
attached thereto, the aryl groups comprising one to three CF.sub.3,
C.sub.6F.sub.5, SO.sub.2CF.sub.3, SO.sub.2C.sub.6F.sub.5 groups and
three to five F atoms, for carbonic acids;, and (iii) a combination
thereof.
11. The method of claim 9, wherein the Bronsted acid is at least
one selected from the group consisting of HCl, HBF.sub.4, and
HSbF.sub.6.
12. The method of claim 2, wherein the organic solvent is at least
one selected from the group consisting of: chlorine-based solvents
including C1-C5 aliphatic hydrocarbons containing 1 to 5 chlorine
atoms; solvents containing C6-C10 aromatic hydrocarbons; solvents
containing C5-C10 aliphatic hydrocarbons; and solvents containing
C1-C8 alcohol, amino, nitrile, and/or nitro groups.
13. The method of claim 2, wherein the organic solvent is at least
one selected from the group consisting of dichloroethane,
dichloromethane, chloroform (trichloromethane), chlorobenzene,
1,2-dichlorobenzene, 1,1,2,2-tetrachloroethane,
1,1,2-trichloroethane, 1,2,3-trichloropropane,
1,1,2,2-tetrachlorethylene, methanol, acetonitrile, toluene, ether,
and hexane
14. The method of claim 2, wherein the amount of the Bronsted
acid-containing catalyst relative to the alkyne compound is 1-40
moil.
15. The method of claim 2, wherein the nucleophile (Nu) is
represented by any one of General Formulas 7 to 9 below.
##STR00033## wherein FG, which is an electron donating group (EDG),
is NR.sub.1R.sub.2, OH, or OR.sub.3, and may be obtained by
combining two or more EDGs with a benzene ring; and R.sub.1 to
R.sub.8 each are independently selected from the group consisting
of hydrogen, deuterium, a C1-C40 alkyl group, a C2-C40 alkenyl
group, a C2-C40 alkynyl group, a C6-C40 aryl group, a heteroaryl
group having 5 to 40 heteronuclear atoms, a C6-C40 aryloxy group, a
C1-C40 alkyloxy group, a C6-C40 arylamine group, a C1-C40
alkylamine group, a C1-C40 alkyl group having C6-C40 aryl, a C1-C40
alkyl group having 1 to 6 alcohol groups, a C1-C40 alkyl group
having C1-C40 amine, a C3-C40 cycloalkyl group, and a
heterocycloalkyl group having 3 to 40 heteronuclear atoms, and
R.sub.1 to R.sub.8 may bind to a neighboring group to form a fused
ring.
16. The method of claim 2, wherein the equivalent ratio of the N--O
bond oxidant to the alkyne compound is in the range of 0.9 to
3.
17. The method of claim 2, wherein the equivalent ratio of the
nucleophile to the alkyne compound is in the range of 1 to 3.5.
18. The method of claim 2, wherein the oxygenative coupling is
performed at 15-50 .quadrature..
19. The method of claim 15, wherein the oxygenative coupling is
performed at 20-30 .quadrature..
20. The method of claim 2, wherein the concentration of the alkyne
compound in the organic solvent is in the range of 0.05-1 M.
Description
1. FIELD OF THE INVENTION
[0001] The present disclosure relates to a method for performing an
oxygenative coupling reaction of alkyne compounds using an acid
catalyst. More specifically, the present disclosure relates to a
method for preparing various physiologically active pharmaceutical
ingredients, such as 1,1-diaryl compounds, 1,1-diheteroaryl
compounds, and 1,4-dicarbonyl compounds, in an economical and
convenient manner under mild conditions without using an expensive
transition metal catalyst by activating an alkyne compound (e.g.,
an ynamide) using a Bronsted acid as a catalyst to induce a
reaction of the activated alkyne compound and a N--O bond oxidant
to form an adduct intermediate and then inducing a coupling
reaction of the adduct intermediate with various nucleophilic
organic compounds (e.g., a nucleophilic arene compound).
2. DESCRIPTION OF THE PRIOR ART
[0002] As an interest of the synthesis of 1,1-diaryl compounds
(e.g., chiral 1,1-diaryl compounds) has recently increased, related
studies have been actively conducted. Specifically, organic
compounds having a 1,1-diaryl structure exhibit various
physiological activities, and examples thereof are known to include
antihistamines, antiarrhythmics, diuretics, antidepressants,
emollients, topical anesthetics, anticholinergics, antimuscarinics,
endothelin antagonists, and the like (e.g., UK-350,926 from
Pfizer).
[0003] It is known that for the synthesis of 1,1-diaryl compounds,
diazo compounds are decomposed by a transition metal (Rh, Cu,
etc.)-catalyzed reaction to form a carbene intermediate. The
synthesis of 1,1-diaryl compounds using diazo compounds has the
risk of explosion and toxicity, and thus, a reaction mechanism in
which a carbene is formed by an oxygenative reaction of alkyne
compounds, specifically, ynamide compounds using a N--O bond
oxidant in the presence of a gold catalyst has been recently
developed (Zhang et al., Org. Biomol. Chem., 2012, 10, 3168).
[0004] In this connection, the foregoing reaction mechanism of the
conventional art may be described as shown in Reaction Scheme
1.
##STR00001##
[0005] However, the methods using metal-carbene intermediates have
the following disadvantages. That is, the carbene intermediates
exhibit various and favorable reactive characteristics, but the
carbene intermediates are very unstable and require very vigorous
reaction conditions. In addition, these methods involve the use of
transition metals, and thus are difficult to apply in the
manufacture of pharmaceutical products, which must satisfy strict
regulations on residual metals, and the synthesis of materials, in
which a trace amount of metal impurities may be problematic. Also,
the kinds of nucleophiles applicable in the coupling reaction are
limited, and thus, various 1,1-diaryl compounds and the like are
difficult to synthesize.
[0006] Meanwhile, in order to solve the limitation of the
conventional art using metal catalysts for the reaction of alkyne
compounds, a reaction route not using a metal has been proposed as
shown in Reaction Scheme 2 below (Gong et al., Angew. Chem. Int.
Ed. 2012, 51, 12307-12310).
##STR00002##
[0007] Although the above-described approach adopts a reaction of
an alkyne compound without using a metal catalyst, an excess amount
of acid is used or the reaction is carried out at a high
temperature. Therefore, the application range of the reaction route
is restricted since the applicable functional groups are limited
and the reaction is implemented by only intramolecular
reactions.
[0008] Accordingly, coupling methods that effectively synthesize
useful compounds, such as 1,1-diaryl compounds, 1,1-diheteroaryl
compounds, and 1,4-dicarbonyl compounds, and that are applied to
various fields using intermediates having equivalent reactivity to
carbene intermediates without using transition metals are
required.
SUMMARY OF THE INVENTION
[0009] According to an aspect of the present disclosure, there is
provided a method for preparing a metal-free and alkyne
compound-derived reactive intermediate, which exhibits equivalent
reactivity to a carbene intermediate, especially, a metal-carbene
intermediate.
[0010] Another aspect of the present disclosure is to provide a
method capable of preparing various compounds, such as 1,1-diaryl
compounds, 1,1-diheteroaryl compounds, and 1,2-dicarbonyl
compounds, under mild conditions by passing through the foregoing
metal-free and alkyne compound-derived reactive intermediate and
conducting an intermolecular coupling reaction of the intermediate
and a wide variety of nucleophiles.
[0011] In accordance with an aspect of the present disclosure,
there is provided a method for preparing an alkyne compound-derived
reactive intermediate, the method including:
[0012] reacting an alkyne compound represented by General Formula 1
with a N--O bond oxidant in the presence of a Bronsted
acid-containing catalyst in an organic solvent to form an
alkyne-oxidant adduct:
##STR00003##
wherein, R.sup.1 is carbonyl (R.sup.4C(O)), sulfonyl
(R.sup.4SO.sub.2), carbamate (R.sup.4OC(O)), or sulfinyl
(R.sup.4S(O)), as a substituent that lowers electron density of N
atoms, and R.sup.4 is selected from the group consisting of a
C1-C40 alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group,
a C6-C40 aryl group, a heteroaryl group having 5 to 40
heteronuclear atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy
group, a C6-C40 arylamine group, a C1-C40 alkylamine group, a
C1-C40 alkyl group having C6-C40 aryl, a C1-C40 alkyl group having
1 to 6 alcohol groups, a C1-C40 alkyl group having C1-C40 amine, a
C3-C40 cycloalkyl group, and a heterocycloalkyl group having 3 to
40 heteronuclear atoms;
[0013] R.sup.2 and R.sup.3 each are independently selected from the
group consisting of hydrogen, deuterium, halogen, a cyano group, a
C1-C40 alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group,
a C6-C40 aryl group, a heteroaryl group having 5 to 40
heteronuclear atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy
group, a C6-C40 arylamine group, a C1-C40 alkylamine group, a
C1-C40 alkyl group having C6-C40 aryl, a C1-C40 alkyl group having
1 to 6 alcohol groups, a C1-C40 alkyl group having C1-C40 amine, a
C3-C40 cycloalkyl group, and a heterocycloalkyl group having 3 to
40 heteronuclear atoms, and R.sup.2 and R.sup.3 may bind to a
neighboring group to form a fused ring; and
[0014] R.sup.1 and R.sup.2 may bind to each other to form an indole
ring, and respective substituents at positions 2, 3, 4, 5, 6, and 7
of the indole are selected from the group consisting of a C1-C40
alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group, a
C6-C40 aryl group, a heteroaryl group having 5 to 40 heteronuclear
atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy group, a C6-C40
arylamine group, a C1-C40 alkylamine group, a C1-C40 alkyl group
having C6-C40 aryl, a C1-C40 alkyl group having 1 to 6 alcohol
groups, a C1-C40 alkyl group having C1-C40 amine, a C3-C40
cycloalkyl group, and a heterocycloalkyl group having 3 to 40
heteronuclear atoms.
[0015] In accordance with another aspect of the present invention,
there is provided a method for oxygenative coupling of an alkyne
compound, the method including:
[0016] reacting an alkyne compound represented by General Formula 1
with a N--O bond oxidant in the presence of a Bronsted
acid-containing catalyst in an organic solvent to form an
alkyne-oxidant adduct intermediate; and
[0017] subsequently reacting the alkyne-oxidant adduct intermediate
with a nucleophile (Nu) to form a compound represented by General
Formula 2 below:
##STR00004##
wherein, R.sup.1 is carbonyl (R.sup.4C(O)), sulfonyl
(R.sup.4SO.sub.2), carbamate (R.sup.4OC(O)), or sulfinyl
(R.sup.4S(O)), as a substituent that lowers electron density of N
atoms, and R.sup.4 is selected from the group consisting of a
C1-C40 alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group,
a C6-C40 aryl group, a heteroaryl group having 5 to 40
heteronuclear atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy
group, a C6-C40 arylamine group, a C1-C40 alkylamine group, a
C1-C40 alkyl group having C6-C40 aryl, a C1-C40 alkyl group having
1 to 6 alcohol groups, a C1-C40 alkyl group having C1-C40 amine, a
C3-C40 cycloalkyl group, and a heterocycloalkyl group having 3 to
40 heteronuclear atoms;
[0018] R.sup.2 and R.sup.3 each are independently selected from the
group consisting of hydrogen, deuterium, halogen, a cyano group, a
C1-C40 alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group,
a C6-C40 aryl group, a heteroaryl group having 5 to 40
heteronuclear atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy
group, a C6-C40 arylamine group, a C1-C40 alkylamine group, a
C1-C40 alkyl group having C6-C40 aryl, a C1-C40 alkyl group having
1 to 6 alcohol groups, a C1-C40 alkyl group having C1-C40 amine, a
C3-C40 cycloalkyl group, and a heterocycloalkyl group having 3 to
40 heteronuclear atoms, and R.sup.2 and R.sup.3 may bind to a
neighboring group to form a fused ring;
[0019] R.sup.1 and R.sup.2 may bind to each other to form an indole
ring, and respective substituents at positions 2, 3, 4, 5, 6, and 7
of the indole are selected from the group consisting of a C1-C40
alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group, a
C6-C40 aryl group, a heteroaryl group having 5 to 40 heteronuclear
atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy group, a C6-C40
arylamine group, a C1-C40 alkylamine group, a C1-C40 alkyl group
having C6-C40 aryl, a C1-C40 alkyl group having 1 to 6 alcohol
groups, a C1-C40 alkyl group having C1-C40 amine, a C3-C40
cycloalkyl group, and a heterocycloalkyl group having 3 to 40
heteronuclear atoms; and
[0020] Nu is selected from the group consisting of a C6-C40
substituted phenol group, a C6-C40 substituted aniline group, an
indole group having 8 to 40 heteronuclear atoms, a pyrrole group
having 5 to 40 heteronuclear atoms, a 1,2-diazole group having 5 to
40 heteronuclear atoms, a C3-C40 silyl enol ether group, and a
C3-C40 terminal vinyl group.
[0021] According to an embodiment, the Bronsted acid may exhibit
acidity with an acid dissociation constant (pKa) in the range of
-10 to 7 in an aqueous solution.
[0022] According to an exemplary embodiment, the Bronsted acid may
be selected, according to the structure of a counter anion, from
the following exemplified kinds: (i) conjugate acids of sulfonate,
bis-sulfonimide, phosphate, phosphoramide, or carboxylate, for
oxygen acids and nitrogen acids; (ii) conjugate acids of carbanions
with aryl groups attached thereto, the aryl groups including one to
three CF.sub.3, C.sub.6F.sub.5, SO.sub.2CF.sub.3,
SO.sub.2C.sub.6F.sub.5 groups and three to five F atoms, for
carbonic acids;, and (iii) a combination thereof.
[0023] According to an exemplary embodiment, the Bronsted acid may
be a super strong acid selected from the group consisting of HCl,
HBF.sub.4, and HSbF.sub.6.
[0024] According to an embodiment, the organic solvent may be
selected from the group consisting of: chlorine-based solvents
including C1-C5 aliphatic hydrocarbons containing 1 to 5 chlorine
atoms; solvents containing C6-C10 aromatic hydrocarbons; solvents
containing C5-C10 aliphatic hydrocarbons; and solvents containing
C1-C8 alcohol, amino, nitrile, and/or nitro groups.
[0025] According to exemplary embodiment, the organic solvent is a
polar solvent, and may be at least one selected from the group
consisting of dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
and dimethylacetamide (DMA).
[0026] According to exemplary embodiment, the organic solvent may
be at least one selected from C1-C10 chain or cyclic ethers.
[0027] In the method according to the specific embodiments of the
present disclosure, when 1,1-diaryl compounds, 1,1-diheteroaryl
compounds, and the like are prepared from an alkyne compound, a
Bronsted acid (or organic acid) catalyst is used to form an adduct
intermediate of an alkyne compound and a N--O bond oxidant, the
adduct intermediate having equivalent reactivity to the existing
metal-carbene intermediate, and the reaction is allowed to pass
through the adduct intermediate, instead of passing through an
existing metal-carbene intermediate, so that the problem due to the
use of a metal catalyst can be avoided. Furthermore, intermolecular
oxygenative coupling reactions using a wide range of nucleophiles
can be performed and high selectivity to target products can be
achieved. Especially, the reduction of yield due to the excessive
oxidation of the alkyne compound during the reaction can be
suppressed as much as possible.
[0028] Therefore, the method according to the specific embodiment
of the present disclosure is not only economical but can also be
applied in the synthesis of organic materials in various fields of
application (medicinal chemistry, agrochemicals, health functional
foods, diagnoses, etc.) as well as basic research fields (biology,
chemical biology, genetics, etc.).
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The above and other objects, features and advantages of the
present invention will be more apparent from the following detailed
description taken in conjunction with the accompanying drawings, in
which:
[0030] FIG. 1 shows oxygenative coupling reaction results with
varying alkyne compounds when indole and pyrrole compounds were
used as nucleophiles;
[0031] FIG. 2 shows oxygenative coupling reaction results when
various arenes, phenols, and silyl enol ethers were used as
nucleophiles;
[0032] FIG. 3 shows possible reaction routes in carrying out an
acid-catalyzed reaction and a metal-catalyzed reaction from
intermediates;
[0033] FIGS. 4a and 4b show HPLC chromatograms of
racemic-pyridine-N-N' dioxide (2g) and chiral pyridine-N-N'
dioxide-(S)-2g), respectively;
[0034] FIGS. 5a and 5b show HPLC analysis results of a racemic
sample (3a) and a sample (3a) obtained using a chiral oxidant (2g),
respectively;
[0035] FIGS. 6a to 6c show chiral HPLC analysis results of products
(3a) obtained in Comparative Examples 1 to 3, respectively;
[0036] FIGS. 7a and 7b show Q-TOF MS analysis results for examining
the presence or absence of adducts in Example 4;
[0037] FIGS. 8a and 8b show .sup.1H NMR spectra of N-Me-indole
(CDCl.sub.3, t1=5 ms) and 3-d-N-Me-indole (98% D, CDCl3, t1=5 ms)
in Example 5, respectively;
[0038] FIG. 8c shows the .sup.1H NMR spectrum of the isotopic
composition of a mixture composed of 300 mol % of N-Me-indole (50%
D) and 5 mol % of HNTf.sub.2(50% D) in Example 5;
[0039] FIG. 8d shows .sup.1H NMR spectrum (CDCl.sub.3, t1=5 ms) of
reference 3a-H in Example 5; and
[0040] FIG. 8e shows .sup.1H NMR spectrum (CDCl.sub.3, t1=5 ms) of
3a-H/D from a reaction product in Example 5.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0041] The present invention can be all accomplished by the
following description. It is to be understood that the following
description illustrates preferable embodiments of the present
invention, but the present invention is not necessarily limited
thereto. It is also to be understood that the accompanying drawings
are included to provide a further understanding of the invention
and are not intended to limit the scope of the invention.
[0042] The terms used herein may be defined as follows.
[0043] The term "adduct" may be understood to mean a chemical
species formed by the addition or condensation of two or more
different compounds or components.
[0044] The term "alkyl group" may mean a monovalent group derived
from a straight-chain or branched-chain saturated hydrocarbon, and
may be substituted or unsubstituted. Examples of the alkyl group
include, but are not limited to, methyl, ethyl, propyl, isobutyl,
sec-butyl, pentyl, iso-amyl, and hexyl.
[0045] The term "alkenyl group" may mean a monovalent group derived
from a straight-chain or branched-chain unsaturated hydrocarbon
having at least one carbon-carbon double bond, and may be
substituted or unsubstituted. Examples of the alkenyl group may
include, but are not limited to, vinyl, allyl, isopropenyl, and
2-butenyl.
[0046] The term "alkynyl group" may mean a monovalent group derived
from a straight-chain or branched-chain unsaturated hydrocarbon
having at least one carbon-carbon triple bond, and may be
substituted or unsubstituted. Examples of the alkynyl group may
include, but are not limited to, ethynyl and 2-propynyl.
[0047] The term "aryl group" may mean a monovalent group derived
from an aromatic hydrocarbon having a single ring or a combination
of two or more rings, and may be substituted or unsubstituted, and
may include a simple pendent or fused form of two or more rings.
Examples of the aryl group may include, but are not limited to,
phenyl, naphthyl, phenanthryl, and anthryl.
[0048] The term "heteroaryl group" may mean a monovalent group
derived from a monoheterocyclic or polyheterocyclic aromatic
hydrocarbon, and may be one in which at least one carbon atom on a
ring is substituted with a heteroatom (e.g., N, O, or S). The
heteroaryl may have a simple pendant or fused form of two or more
rings, and may be understood to include a fused form with an aryl
group. In addition, the heteroaryl group may be substituted or
unsubstituted. Examples of the heteroaryl group may include, but
are not limited to: 6-membered monocyclic rings, such as pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl; polycyclic
rings, such as phenoxathienyl, indolizinyl, indolyl, purinyl,
quinolyl, benzothiazole, and carbazolyl; and 2-furanyl,
N-imidazolyl, 2-isoxazolyl, 2-pyridinyl, and 2-pyrimidinyl.
[0049] The term "aryloxy group" may be a monovalent group including
all --O-aryl groups and --O-heteroaryl groups, may be substituted
or unsubstituted. Examples of the aryloxy group may include, but
are not limited to, phenyloxy, naphthyloxy, and diphenyloxy.
[0050] The term "alkyloxy group" may mean a monovalent group having
an --O-alkyl group and may be understood to include all
straight-chain, branched chain, or cyclic structure, and may be
substituted or unsubstituted. Examples of the alkyloxy group may
include, but are not limited to, methoxy, ethoxy, n-propoxy,
1-propoxy, t-butoxy, n-butoxy, and pentoxy.
[0051] The "arylamine group" may mean an amine group substituted
with aryl.
[0052] The term "cycloalkyl group" may mean a monovalent group
derived from a monocyclic or polycyclic non-aromatic hydrocarbon,
and may be substituted or unsubstituted. Examples of the cycloalkyl
group may include, but are not limited to, cyclopropyl,
cyclopentyl, cyclohexyl, and norbornyl.
[0053] The term "heterocyclic group" may mean a saturated or
unsaturated group having a single ring or multiple fused rings, in
which at least one carbon in a ring is substituted with a
heteroatom (e.g., N, O, or S) to form a ring skeleton. The
heterocyclic group may be substituted or unsubstituted, and
examples thereof may include, but are not limited to, pyrrole,
pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, and
tetrazole.
[0054] The term "heterocycloalkyl group" may mean a monovalent
cycloalkyl group derived from a non-aromatic hydrocarbon, in which
at least one carbon atom of a ring is substituted with a heteroatom
(e.g., N, O, or S). The heterocycloalkyl group may be substituted
or unsubstituted, and examples thereof may include, but are not
limited to, morpholine and piperazine.
[0055] The term "alkylsilyl group" may mean a silyl group
substituted with alkyl.
[0056] The term "arylsilyl group" may mean a silyl group
substituted with aryl.
[0057] The term "silyl enol ether" may mean a group in which oxygen
at the end of an enolate is bonded to an organosilicon group.
[0058] The term "halogen" may mean at least one halogen atom or
substituent, and examples thereof may include fluorine, bromine,
chlorine, or iodine.
[0059] The term "dihalogen" may be two substituents, each of which
is independently selected from the group consisting of fluorine,
bromine, chlorine, or iodine.
[0060] According to an embodiment of the present disclosure, for
the intermolecular oxygenative C--C coupling reaction of an alkyne
compound and a nucleophile, a Bronsted acid-catalyzed reaction is
used to induce an intermolecular Friedel-Crafts type addition
reaction into an umpolung enolate formed from an alkyne compound as
a substrate. For this, the strategy of passing through an adduct
intermediate of an alkyne compound and a N--O bond oxidant, the
adduct being formed using a Bronsted acid as a catalyst, is
proposed. That is, an alkyne compound, especially, an ynamide
compound may be a suitable precursor of keteniminium ions under the
Bronsted acid-catalyzed reaction due to the easily polarized triple
bond. Here, for the intermolecular coupling reaction, it is
necessary to not only minimize side reactions, such as hydration,
and over-oxidation by a N--O bond oxidant, but also to control
chemoselectivity among potential nucleophile to keteniminium salts
(e.g., nucleophilic arene), counter bases of acid catalysts, and
solvents (e.g., halogenated solvent).
[0061] According to an embodiment of the present disclosure, the
keteniminium salt is allowed to selectively pass through sequential
routes of the formation of an adduct of an alkyne compound and a
N--O bond oxidant and the subsequent attack by a nucleophile, and
this procedure is similar to a conventional case using the
reactivity of a carbene (i.e., .alpha.-oxo carbene).
[0062] Without being bound to a particular theory, such an
oxygenative coupling reaction is based on the S.sub.N2' reaction
mechanism in which the N--O coupling cleavage of an oxidant occurs
together with the attack by a nucleophile.
[0063] The adduct is a potent electrophile, and may easily induce a
Friedel-Crafts type intermolecular coupling reaction with a wide
range of C-nucleophiles (e.g., indoles, pyrroles, anilines,
phenols, silyl enol ethers, etc.).
[0064] In an embodiment, the alkyne compound may be an ynamide
compound represented by General Formula 1 below:
##STR00005##
wherein, R.sup.1 is carbonyl (R.sup.4C(O)), sulfonyl
(R.sup.4SO.sub.2), carbamate (R.sup.4OC(O)), or sulfinyl
(R.sup.4S(O)), as a substituent that lowers electron density of N
atoms, and R.sup.4 is selected from the group consisting of a
C1-C40 alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group,
a C6-C40 aryl group, a heteroaryl group having 5 to 40
heteronuclear atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy
group, a C6-C40 arylamine group, a C1-C40 alkylamine group, a
C1-C40 alkyl group having C6-C40 aryl, a C1-C40 alkyl group having
1 to 6 alcohol groups, a C1-C40 alkyl group having C1-C40 amine, a
C3-C40 cycloalkyl group, and a heterocycloalkyl group having 3 to
40 heteronuclear atoms;
[0065] R.sup.2 and R.sup.3 each are independently selected from the
group consisting of hydrogen, deuterium, halogen, a cyano group, a
C1-C40 alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group,
a C6-C40 aryl group, a heteroaryl group having 5 to 40
heteronuclear atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy
group, a C6-C40 arylamine group, a C1-C40 alkylamine group, a
C1-C40 alkyl group having C6-C40 aryl, a C1-C40 alkyl group having
1 to 6 alcohol groups, a C1-C40 alkyl group having C1-C40 amine, a
C3-C40 cycloalkyl group, and a heterocycloalkyl group having 3 to
40 heteronuclear atoms, and R.sup.2 and R.sup.3 may bind to a
neighboring group to form a fused ring; and
[0066] R.sup.1 and R.sup.2 may bind to each other to form an indole
ring, and respective substituents at positions 2, 3, 4, 5, 6, and 7
of the indole are selected from the group consisting of a C1-C40
alkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group, a
C6-C40 aryl group, a heteroaryl group having 5 to 40 heteronuclear
atoms, a C6-C40 aryloxy group, a C1-C40 alkyloxy group, a C6-C40
arylamine group, a C1-C40 alkylamine group, a C1-C40 alkyl group
having C6-C40 aryl, a C1-C40 alkyl group having 1 to 6 alcohol
groups, a
[0067] C1-C40 alkyl group having C1-C40 amine, a C3-C40 cycloalkyl
group, and a heterocycloalkyl group having 3 to 40 heteronuclear
atoms.
[0068] According to a more specific embodiment, in the formula
above, R.sup.1 may be methylsulfonyl (Ms) or tosyl (Ts); R.sup.2
may be methyl, benzyl, or allyl; and R.sup.3 may be p-methoxyphenyl
(PMP), 2,4,6-methyl phenyl (Mes), or 3,4-dimethoxyphenyl.
[0069] The foregoing alkyne compound may react with an oxidant
having a particular bond in the presence of an acid catalyst,
specifically a Bronsted acid-containing catalyst, in a solvent
(specifically, an organic solvent) to form an adduct intermediate,
and such an adduct intermediate may be subjected to a coupling
reaction with a nucleophile (Nu) to synthesize a product
represented by General Formula 2 below:
##STR00006##
wherein R.sup.1, R.sup.2 and R.sup.3 are as described above; and Nu
may be selected from the group consisting of a C6-C40 substituted
phenol group, a C6-C40 substituted aniline group, an indole group
having 8 to 40 heteronuclear atoms, a pyrrole group having 5 to 40
heteronuclear atoms, a 1,2-diazole group having 5 to 40
heteronuclear atoms, a C3-C40 silyl enol ether group, and a C3-C40
terminal vinyl group.
[0070] In the above-described oxygenative coupling reaction, a kind
of solvent that can act as a reaction medium of an alkyne compound
and an oxidant as reactants and an acid catalyst may be used.
[0071] In this connection, a usable solvent may be selected from
the group consisting of: chlorine-based solvents including C1-C5
aliphatic hydrocarbons containing 1 to 5 chlorine atoms; solvents
containing C6-C10 aromatic hydrocarbons; solvents containing C5-C10
aliphatic hydrocarbons; and solvents containing C1-C8 alcohol,
amino, nitrile, and/or nitro groups. These organic solvents may be
used alone or in a combination of two or more thereof as a mixed
solvent.
[0072] According to exemplary embodiment, the organic solvent is a
polar solvent, and may be at least one selected from the group
consisting of dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
and dimethylacetamide (DMA).
[0073] According to another exemplary embodiment, the organic
solvent may be at least one selected from C1-C10 chain or cyclic
ethers.
[0074] In a particular embodiment, the organic solvent may be at
least one selected from the group consisting of dichloroethane,
dichloromethane, chloroform (trichloromethane), chlorobenzene,
1,2-dichlorobenzene, 1,1,2,2-tetrachloroethane,
1,1,2-trichloroethane, 1,2,3-trichloropropane,
1,1,2,2-tetrachlorethylene, methanol, acetonitrile, toluene, ether,
and hexane. Specifically, dichloroethane, dichloromethane,
1,2-dichlorobenzene, 1,1,2,2-tetrachloroethane,
1,1,2-trichloroethane, 1,2,3-trichloropropane, toluene, ether,
hexane, or a combination thereof may be used. More specifically,
dichloroethane, dichloromethane, 1,1,2-trichloroethane, or a
combination thereof may be used.
[0075] According to an exemplary embodiment, the concentration of
the alkyne compound in a reaction medium (organic solvent) may be
in the range of, for example, about 0.05-1 M, specifically about
0.1-0.8 M, and more specifically about 0.2-0.7 M. Since excessively
high or low reactant concentrations may reduce the yield of a
target product (coupled reaction products), it may be advantageous
to properly adjust the concentration of the reactant within the
above-described range.
[0076] In an embodiment, the catalyst may be a catalyst containing
a Bronsted acid. Here, the Bronsted acid may exhibit acidity with
an acid dissociation constant (pKa) of, for example, about -10 to
7, specifically, -5 to 4, and more specifically, -1 to 2, in an
aqueous solution.
[0077] According to an exemplary embodiment, at least one of acids
exemplified as below may be used as a Bronsted acid according to
the structure of a counter anion of the Bronsted acid: (i)
conjugate acids of sulfonate, bis-sulfonimide, phosphate,
phosphoramide, or carboxylate, for oxygen acids and nitrogen acids;
(ii) conjugate acids of carboanions with aryl groups attached
thereto, the aryl groups including one to three CF.sub.3,
C.sub.6F.sub.5, SO.sub.2CF.sub.3, SO.sub.2C.sub.6F.sub.5 groups and
three to five F atoms, for carbonic acids;, and (iii) a combination
thereof.
[0078] Alternatively, the Bronsted acid may be a super strong acid,
and thus examples thereof may be at least one selected from the
group consisting of HCl, HBF.sub.4, and HSbF.sub.6.
[0079] For example, Tf.sub.2NH, TfOH, HBF.sub.4.OEt.sub.2, and a
mixture of HNTf.sub.2 and 2-Cl-pyridine may be used alone or in
combination of two or more thereof as a Bronsted acid.
Specifically, Tf.sub.2NH, a mixture of HNTf.sub.2 and
2-Cl-pyridine, TfOH, or a combination thereof may be used, and more
specifically, Tf.sub.2NH and/or a mixture of HNTf.sub.2 and
2-Cl-pyridine may be used.
[0080] According to an exemplary embodiment, the amount of the
Bronsted acid-containing catalyst to the alkyne compound may be in
the range of, for example, about 1-40 mol %, specifically about
1.5-35 mol %, and more specifically about 2-10 mol %. The amount of
the catalyst in the reaction medium greatly affects the formation
of the adduct and thus may be controlled within the above-described
range, but is not limited thereto. The amount of the catalyst may
be varied according to the alkyne compound, the N--O bond oxidant,
and the like.
[0081] Meanwhile, according to a specific embodiment of the present
disclosure, the N--O bond oxidant may be used as an oxidant to the
alkyne compound. For example, the N--O bond oxidant may be
represented by General Formula 3 or 4 below:
##STR00007##
wherein R, R', and R'' each may be a C1-C40 heteroaryl compound
forming a ring together with N, and may also be a compound having
axial chirality in which the rotation of a R'--R'' bond is
restricted according to the substituent.
[0082] According to an exemplary embodiment, the N--O bond oxidant
may be represented by General Formula 5 below:
##STR00008##
wherein R''' is hydrogen, a halogen, a dihalogen, a cyano group, an
alkoxy group, or a nitro group.
[0083] More specifically, R''' may be hydrogen, 2-chloro, 2-bromo,
2-methoxy, 4-nitro, 2,4-dichloro, 2,6-dichloro, 2,6-dibromo or
3,5-dibromo.
[0084] According to an exemplary embodiment, the foregoing oxidant
represented by General Formula 3 may react with an alkyne compound
of General Formula 1 in the presence of an acid catalyst to form an
adduct represented by General Formula 6 below:
##STR00009##
[0085] R.sup.1, R.sup.2, R.sup.3 and R are as described above.
[0086] According to an exemplary embodiment, the N--O bond oxidant
having chirality may be used to obtain a reaction product having
optical activity.
[0087] Meanwhile, in an embodiment according to the present
disclosure, the formation of the adduct and the coupling reaction
with the nucleophile may be carried out through a single stage. For
example, in cases where pyridine-N-oxide is used as a N--O bond
oxidant, the oxygenative coupling reaction may be carried out
through a route according to Reaction Scheme 3 below:
##STR00010##
[0088] According to the reaction scheme above, during the
oxygenative coupling reaction, a nucleophile and R.sup.3 are bonded
at the 1,1-position and a carbonyl group is formed at a neighboring
position. Specifically, in the case where R.sup.3 and Nu are an
aryl group, 1,1-diaryl compound (specifically, 1,1-diaryl carbonyl
compound) may be formed. As described above, the nucleophile (Nu-H)
used for the coupling reaction may include various indoles,
pyrroles, anilines, phenols, silyl enol ethers, and the like, and
may be represented by, for example, General Formulas 7 to 9
below:
##STR00011##
wherein FG, which is an electron donating group (EDG), is
NR.sub.1R.sub.2, OH, or OR.sub.3, and may be obtained by combining
two or more EDGs with a benzene ring; and
[0089] R.sub.1 to R.sub.8 each are independently selected from the
group consisting of hydrogen, deuterium, a C1-C40 alkyl group, a
C2-C40 alkenyl group, a C2-C40 alkynyl group, a C6-C40 aryl group,
a heteroaryl group having 5 to 40 heteronuclear atoms, a C6-C40
aryloxy group, a C1-C40 alkyloxy group, a C6-C40 arylamine group, a
C1-C40 alkylamine group, a C1-C40 alkyl group having C6-C40 aryl, a
C1-C40 alkyl group having 1 to 6 alcohol groups, a C1-C40 alkyl
group having C1-C40 amine, a C3-C40 cycloalkyl group, and a
heterocycloalkyl group having 3 to 40 heteronuclear atoms, and
R.sub.1 to R.sub.8 may bind to a neighboring group to form a fused
ring.
[0090] In this connection, as the reaction temperature is
excessively low or increased during the oxygenative coupling
reaction (i.e., the formation of an adduct of an alkyne compound
and a N--O bond oxidant and the coupling with a nucleophile)
according to a specific embodiment of the present disclosure, the
yield of a target produce decreases, and thus it is advantageous to
adjust the reaction temperature to an appropriate range. According
to an embodiment, the reaction temperature may be about
15-50.degree. C., specifically about 17-40.degree. C., and more
specifically about 20-30.degree. C., and especially room
temperature. However, the temperature range is provided for the
exemplary purpose, and thus the present invention is not
necessarily limited to the temperature range.
[0091] It is noteworthy that the reaction can be carried out under
mild reaction conditions, even at room temperature, through a
catalyst reaction using a Bronsted acid. The temporal
chemoselectivity can be effectively improved during the
intermolecular coupling reaction through such mild reaction
conditions, and thus a reaction route with high selectivity can be
provided at a significantly low temperature compared with the
conventional art requiring a comparatively high reaction
temperature.
[0092] According to an exemplary embodiment, in cases where the
amounts of the N--O bond oxidant and/or the nucleophile are
excessively small or great compared with the alkyne compound as a
substrate in the oxygenative coupling reaction, the yields of
target products may be reduced. Therefore, according to an
exemplary embodiment, the equivalent ratio of the N--O bond oxidant
to the alkyne compound may be in the range of, for example, about
0.9-3, specifically about 1-2.5, and more specifically about
1.2-2.
[0093] In addition, the equivalent ratio of the nucleophile to the
alkyne compound may be in the range of, for example about 1-3.5,
specifically about 1.2-3.2, and more specifically about 1.5-3.
However, the numerical ranges are provided for illustration, and
thus the present invention is not necessarily limited thereto.
[0094] According to a specific embodiment, the equivalent ratio of
alkyne compound: N--O bond oxidant : nucleophile may be in the
range of, for example, 1: about 1.7-2.3: about 2.7-3.3,
specifically 1: about 1.8-2.2: about 2.8-3.2, and more specifically
1: about 1.9-2.1: about 2.9-3.1.
[0095] According to an exemplary embodiment, the oxygenative
coupling reaction time may be varied according to the kind of
alkaline compound, the kind of oxidant, the kind of nucleophile,
the concentrations of reactants, the reaction temperature, and the
like. However, in the case of a highly reactive nucleophile, the
oxygenative coupling reaction time on the basis of room temperature
may be in the range of, for example about 15 minutes to 24 hours,
specifically about 30 minutes to 18 hours, and more specifically
about 1 hour to 12 hours. Alternatively, in the case of a reaction
using a relatively low reactive nucleophile (e.g., a silyl enol
ether), the oxygenative coupling reaction time may be described on
the basis of a temperature higher than room temperature (e.g.,
about 80 .quadrature.), and thus the oxygenative coupling reaction
time may be in the range of, for example, about 2-48 hours,
specifically about 5-36 hours, and more specifically about 10-24
hours. However, it should be noted that, as for a highly reactive
nucleophile (e.g., a phenol nucleophile), the use of an existing Au
catalyst requires the above-described reaction time at a high
temperature (e.g., 80 .quadrature.) in order to induce an
oxygenative coupling reaction, but on the reaction route according
to a specific embodiment of the present disclosure, the reaction
can be carried out within the above-described reaction time range
even in the mild conditions, such as room temperature.
[0096] As described above, in the specific embodiment according to
the present disclosure, an adduct of an alkyne compound and a N--O
bond oxidant, which is formed in the presence of an acid catalyst,
is used as a substitute for a carbene intermediate (i.e., a-oxo
carbene) for a C--C coupling-forming intermolecular coupling
reaction between an alkyne compound and a nucleophile. As described
above, the coupling reaction using an acid catalyst is performed
under the mild temperature conditions, thereby increasing temporal
chemoselectivity in the nucleophiles in the reaction system.
Especially, a coupling reaction between two stereoselective (or
enantioselective) molecules can be performed via the oxidation of
the alkyne compound by using a chiral compound (e.g., chiral
N,N'-dioxide) as a N--O bond oxidant.
[0097] The present invention can be more clearly understood by the
following examples, and these examples are merely illustrative of
the present invention and are not intended to limit the scope of
the invention.
EXAMPLE 1
[0098] In the present example, an oxygenative coupling reaction of
an alkyne compound was carried out through two procedures below
according to the nucleophile.
[0099] Materials and Measuring Devices
[0100] All solvents were dried and distilled according the standard
method descried in Armarego, W. L. F.; Chai, C. L. L. Purification
of Laboratory Chemicals; Elsevier: Oxford, 2009 prior to use.
Pyridine-N-oxide and ynamide each were prepared according to the
procedure on the literatures (Antonchick, A. P.; Org. Lett. 2015,
17, 3134 and Gillie, A. D.; Reddy, R. J.; Davies, P. W. Adv. Synth.
Catal. 2016, 358, 226)
[0101] All other chemicals were purchased in the market and used as
purchased.
[0102] Thin-layer chromatography (TLC) analysis was performed on
the Merck silica gel 60 F254 TLC plate, and visualized using a UV
lamp and a KMnO4 solution.
[0103] Flash chromatography was performed on Kieselgel 60 (230-400
mesh).
[0104] .sup.1H and .sup.13C NMR spectra were recorded on a Bruker
(400 MHz) spectrometer with TMS.
[0105] High resolution mass spectrometry (HRMS) was obtained from
Korea Basic Science Institute (KBSI, Daegu).
[0106] The optical purity analysis was performed on Shimadzu HPLC
(LC-20A Prominence Series) using Chiralpak.RTM. IA and Chiralcel
OJ-H columns (5 .mu.m particle size, 4.6 mm.times.250 mm) and
isopropyl alcohol and n-hexane as mobile phases.
[0107] Q-TOF mass spectrum was measured on the Agilent 6545 series
Q-TOF instrument.
[0108] Experimental Procedures
[0109] A. Experimental Procedure 1 (Products 3 and 7)
[0110] The present experimental procedure was performed according
to Reaction Scheme 4 below.
##STR00012##
[0111] A screw cap vial was filled with a solution in which an
ynamide (1a) (23.9 mg, 0.10 mmol), 2-chloropyridine N-oxide (2a)
(25.9 mg, 0.20 mmol), and N-methyl indole (39.3 mg, 0.30 mmol) were
dissolved in DCM (0.2 ml, 0.5 M). HNTf2 (2.8 mg, 0.010 mmol) was
added to the mixture, and the resulting mixture was stirred at room
temperature (23 .quadrature.). Upon the completion of the reaction
(determined by TLC monitoring), the crude reaction mixture was
directly loaded onto a silica column, and purified by flash
chromatography (eluent: hexane/ethyl acetate=2:1) to give compound
3a (35.2 mg, 91%) as a viscous oil.
[0112] B. Experimental Procedure B (Product 8)
[0113] The present experimental procedure was performed according
to Reaction Scheme 5 below.
##STR00013##
[0114] The experimental procedure was performed in the same manner
as Experimental procedure A except that the nucleophile was
replaced with t-butyl dimethyl ((1-phenylvinyl)oxy)silane (70.3
mg). Upon the completion of the reaction (TLC), the crude mixture
was hydrolyzed by the addition of 1N HCl (1 mL) aqueous solution,
followed by vigorous stirring at room temperature for 30 minutes.
The aqueous solution phase was extracted with ether (1 mL,
.times.3), and the combined organic phase was dried (MgSO.sub.4),
concentrated, and purified by flash chromatography (eluent:
hexane/ethyl acetate=2:1) to give compound 8a (28.9 mg, 77%) as a
viscous oil. As for compounds 8a, 8d and 8e, the diastereomeric
ratio was determined from crude NMR after hydrolysis (dr
3.6/1).
[0115] Selection of Acid Catalyst
[0116] The reaction.sup.a was performed according to Reaction
Scheme 6 below, and the results are shown in Table 1 below.
##STR00014##
TABLE-US-00001 TABLE 1 Reaction Yield (%) Entry Acid (HX)
conditions (3a/4a/5a) 1 HCOOH 80.degree. C., 24 h 0/25/20 2
PhCO.sub.2H 80.degree. C., 24 h 0/17/32 3 MsOH 80.degree. C., 8 h
53/8/6 4 TsOH.cndot.H.sub.2O 60.degree. C., 4.5 h 59/14/0 5 TfOH
RT, 2 h 76/6/0 6 HBF.sub.4.cndot.OEt.sub.2 RT, 1.5 h 68/9/0 7
HNTf.sub.2 RT, 25 min 79/0/0 .sup. 8.sup.b HNTf.sub.2 RT, 15 min
89/0/0 .sup. 9.sup.b, c HNTf.sub.2, 2-Cl-pyr RT, 15 min 87/0/0
.sup. 10.sup.b, d HNTf.sub.2 RT, 12 h 75/0/0 .sup.a Unless
otherwise mentioned, an ynamide (1a) (0.1 mmol), 2-chloropyridine
N-oxide (2a) (0.2 mmol), and N--Me-indole (0.3 mmol) were reacted
in DCE (0.1M). The yield was measured by .sup.1H NMR spectrum.
.sup.b0.5M DCE was used. .sup.cA mixture of HNTf.sub.2 and
2-Cl-pyridine (1:1, each 10 mol %) was used as a catalyst.
.sup.d2.5 mol % of HNTf.sub.2 was used.
[0117] According to the table above, it was verified that
HNTf.sub.2 was the most suitable acid catalyst (see Entries 1-7) as
a result of testing various Bronsted acids. Weak acids required a
higher temperature and longer reaction time in the conversion
reaction, and induced a hydration reaction (4a) as a competitive
reaction. In the case where the concentration was increased, the
reaction time was further reduced, and thus a yield of 89% was
obtained in 15 minutes at room temperature (Entry 8).
[0118] Actually, the use of 2-Cl-pyridinium NTf.sub.2 salt (10 mol
%) was effective for all the cases (Entry 8 and entry 9 on Table
1). In addition, a lowered amount of the acid catalyst (2.5 mol %)
took 12 hours at room temperature until the reaction was completed,
but the yield of compound 3a was 75%, which was still high.
[0119] It can be seen from the above-described experimental results
that the optimized conditions in the present disclosure are milder
than a gold-catalyzed reaction or conventional acid-mediated
conditions (typically, high-temperature conditions of about 80
.quadrature.) and/or a stoichiometric amount of acid. As a result,
excessive oxidation or hydration, which often occurs at a higher
temperature, was not observed.
[0120] Selection of Oxidant
[0121] Since the reaction efficiency is highly dependent on the
structure of a pyridine-N-oxide oxidant, the reaction was carried
out according to Reaction Scheme 7 below with different kinds of
oxidants for the selection of a suitable oxidant. The results are
shown in Table 2 below.
##STR00015##
[0122] Here, the N--O bond oxidants are shown in General Formula 10
below.
##STR00016##
TABLE-US-00002 TABLE 2 Reaction Yield (%) Entry N--O oxidant
conditions (3b/4b/5b) 1 2a RT, 15 min 89/0/0 2 2b RT, 30 min 80/0/0
3 2c RT, 30 min 77/0/0 4 2d RT, 30 min 70/0/0 5 2e 80.quadrature.,
4 h 58/0/0 6 2f 60.quadrature., 3 h 75/0/0 .sup.a An ynamide (1a)
(0.1 mmol), N-oxide (2) (0.2 mmol), and N--Me-indole (0.3 mmol)
were reacted in DCE (0.5M). The yield was measured by .sup.1H NMR
spectrum.
[0123] According to the table above, considering that one
equivalent of pyridine released in the mixture buffered an acid
catalyst, a lower basic pyridine (pKa=0.49 for 2-Cl-pyridinium
salt) was important.
[0124] Evaluation of Reaction Characteristics According to Alkyne
Compound
[0125] In cases where indoles and pyrroles were used as
nucleophiles under the optimized reaction conditions as described
above, reaction characteristics with varying alkyne compounds were
evaluated. For this, the reaction.sup.[a] was carried out according
to Reaction Scheme 8 below using various indoles and pyrroles as
nucleophiles, and the results are shown in FIG. 1 ([a]: Unless
otherwise mentioned, an ynamide (1) (0.1 mmol), 2-chloropyridine
N-oxide (2a) (0.2 mmol), and indole/pyrrole (0.3 mmol) were reacted
in the presence of HNTf.sub.2 (10 mol %) in DCE (0.5 M): The
isolated yield was obtained after chromatography;
PMP(p-MeO--C.sub.6H.sub.4), Mes (2,4,6-Me.sub.3-C.sub.6H.sub.2.);
[b] 1.5 eq. of 1, 2-dimethyl indole was used).
##STR00017##
[0126] A series of ynamide substrates were effectively subjected to
a coupling reaction to produce corresponding 1,1-diarylamide
compounds (3). The reaction was somewhat sensitive to electronic
characteristics of the Ar group at R.sup.3, but showed reasonable
product yields (3b to 3g). It is noteworthy that even in cases of
bulky aryl groups, excellent yields of products (3d and 3g) were
obtained without delaying the reaction.
[0127] It was verified that all the ynamides having Bn (3i),
N-allyl (3j), and alkyl (3k) at R.sup.2 and ynamides having
3-thienyl (3I) at R.sup.3 (pharmaceutically important) were
suitable substrates. In addition, pyrroles (3p, 3q, and 3r),
N-unsubstituted indoles (3m and 3o) and 1,2-dimethylindole (3n)
were also successfully converted at room temperature, and could be
synthesized at high yields (or high yields and selectivity) for a
short time. Here, it is interesting that ynamides (3r and 3s) are
excellent substrates.
[0128] Meanwhile, for the product (3n), the use of 3 eq. of the
nucleophile resulted in the direct formation of a significant
amount of arylation products, thereby reducing the amount of the
nucleophile, thus increasing the yield.
[0129] Evaluation of Effects of Nucleophiles
[0130] Based on the successful coupling reaction with indoles and
pyrroles, it was evaluated whether the oxygenative alkyne-arene
coupling reaction was also applicable to a relatively less
nucleophilic arene. For this, the reaction.sup.[a] was carried out
according to Reaction Scheme 9 below using an arene, a phenol, and
a silyl enol ether as nucleophiles, and the results are shown in
FIG. 2. ([a]: an ynamide (1) (0.1 mmol), 2-Cl-pyridine-N-oxide (2a)
(0.2 mmol), and arene/phenol/silyl enol ether (0.3 mmol) were
reacted in the presence of HNTf2 (10 mol %) in DCE (0.5 M): The
isolated yield was obtained after chromatography; [b] Crude
products were hydrolyzed with a 1 N hydrochloric acid aqueous
solution prior to purification; and [c] (Z)-silyl enol ether was
used).
##STR00018##
[0131] As a result of the Friedel-Crafts type alkylation of
N,N-dimethyl aniline as a nucleophile, the products (7a to 7b) were
produced with favorable yields and positional selectivity. However,
the reaction rate was slow for a relatively less nucleophilic
alkoxy arene (7c).
[0132] In addition, a favorable coupling reaction was achieved for
the phenol. In the cases where o- or m-guaiacol (7d, 7e),
1-naphthol (7f), phenol (7h), catechols (7i to 7l) and even
sterically demanding phenol (7g) were used, the respective coupled
products could be obtained efficiently as single regioisomers.
[0133] Subsequently, it was examined whether such approach could
also be applied to the preparation of 1,4-dicarbonyl compounds.
With silyl enol ether as a nucleophile, 1,4-dicarbonyl compounds
(8a to 8f) were obtained after hydrolysis. For 2-substituted silyl
enol ethers (8d to 8f), the products were obtained as a mixture of
diastereomers (dr 3.6/1 to 1.6/1).
EXAMPLE 2
[0134] Identification of Reaction Mechanism
[0135] A mechanism by which an alkyne compound is oxidized by
pyridine-N-oxide through a Bronsted acid-catalyzed reaction was
identified. In this connection, possible reaction routes in
carrying out an acid-catalyzed reaction and a metal-catalyzed
reaction from an intermediate are shown in FIG. 3.
[0136] According to the previous studies, it has been known that,
under the Bronsted acid or Lewis acid conditions, the
ynamide/pyridine-N-oxide adduct (A) passed through a carbene route
(based on the 1,2-hydride shift), a phenylium ion, or a concerted
S.sub.N2' route during the N--O coupling redox reaction. The former
two reaction routes are distinguished from the other route in that
the N--O bond cleavage occurs prior to the attack by an arene.
Therefore, when the enantio-induction using chiral pyridine-N-oxide
was observed, such a product may serve as a test for the concerted
S.sub.N2' mechanism.
[0137] An oxidation conversion reaction was carried out using the
chiral bipyridine-N,N'-dioxide of Nakajima as shown in Reaction
Scheme 10 below.
##STR00019##
[0138] First, according to a known procedure, chiral pyridine-N-N'
dioxide (S)-2g was prepared by using (R,R)-dibenzoyl-L-tartaric
acid as a chiral decomposing agent and employing the
chromatographic separation of diastereoisomeric salts as shown in
Reaction Scheme 11 below (Nakajima, M.; Shiro, M.; Hashimoto, S.
Tetrahedron: Asymmetry 1997, 8, 341).
##STR00020##
[0139] HPLC chromatograms of racemic-2g and (S)-2g are shown in
FIGS. 4A and 4B. The optical purity (enantiopurity) was determined
by chiral HPLC analysis ((96% ee, Chiralcel OJ-H,
n-hexane/iPrOH=2:1); [a] D-122 (c=1.0, CHCl.sub.3)).
[0140] A. Preparation of Racemic Sample (3a)
[0141] A racemic sample was prepared according to Experimental
Procedure 1. Chiral analysis was performed on the Chiralpak.RTM. IC
column using IPA: n-hexane (40:60) as eluent (1 mL/min). The
results are shown in FIG. 5A.
[0142] B. Preparation of Product (3a) by Bronsted -Acid Catalyzed
Reaction Using Chiral Oxidant (2g)
[0143] A sample was prepared according to Experimental Procedure 1,
and 2-Cl-pyridine-N-oxide (2a) was substituted with a chiral
oxidant (2g; 2 eq., 200 mol %). The reaction was carried out at 23
.quadrature. for 2 hours, and the separation by chromatography gave
a yield of 94%. Chiral HPLC analysis was performed using the
Chiralpak.RTM. IC column (83.2% ee). The results are shown in FIG.
5B. The mono-N-oxide (2g') (38%) was recovered together with
unreacted N-N'-dioxide (2g; 104%), and was determined to have 6.2%
ee using the chiral decomposition method by Kim et al (J. Am. Chem.
Soc. 2015, 137, 14190).
[0144] However, the use of mono-N-oxide (2g') instead of di-N-oxide
(2g) as an oxidant resulted in a very slow conversion reaction even
though the other conditions are the same, and 52% of the product
(3a) was formed at room temperature after 24 hours.
[0145] According to the above-described experimental results, when
the ynamide (1a) was reacted with the stereo-rich compound (s)-2g
(200 mol %) in the presence of the HNTf.sub.2 catalyst, the product
(3a) could be separated with a high yield (94%) and favorable
stereoselectivity (83% ee), which directly supports that the
reaction proceeded through the concerted S.sub.N2' route.
Particularly, the foregoing experiment is significant in that the
experimental results first reported a stereoselective
intermolecular coupling reaction through alkyne oxidation.
COMPARATIVE EXAMPLES 1 to 3
[0146] A product (3a) was prepared under the gold (Au) and zinc
(Zn)-catalyzed reaction conditions through the reaction route shown
in Reaction Scheme 10.
COMPARATIVE EXAMPLE 1
[0147] Reaction using IPrAuNTf.sub.2 at Room Temperature
[0148] The reaction was carried out in the presence of
IPrAuNTf.sub.2 as a gold catalyst according to Reaction Scheme 12
below.
##STR00021##
[0149] The reaction was carried out according to Experimental
Procedure 1 except that 2-Cl-pyridine-N-oxide (2a) was replaced
with an oxidant (2g; 2 eq., 200 mol %) and 10 mol % of HNTf.sub.2
was substituted with 5 mol % of IPrAuNTf2. The reaction was carried
out at 23 .quadrature. for 45 hours, and the separation by
chromatography gave a yield of 84%. Chiral HPLC analysis was
performed using the Chiralpak.RTM. IC column (81.7% ee). The
results are shown in FIG. 6A.
COMPARATIVE EXAMPLE 2
[0150] Reaction Under Conditions of Aqueous Solution Medium,
Reaction Temperature of 80 .quadrature., and IPrAuNTf.sub.2
Catalyst
[0151] The reaction was carried out in the presence of
IPrAuNTf.sub.2 as a gold catalyst according to Reaction Scheme 13
below.
##STR00022##
[0152] A product (3a) was synthesized by the same method as in
Comparative Example 1 except that water (0.5 M) was used as the
solvent and the reaction temperature was set to 80 .quadrature..
The reaction was carried out for 45 hours, and the separation by
chromatography gave a yield of 76%. Chiral HPLC analysis was
performed using the Chiralpak.RTM. IC column (70.8% ee). The
results are shown in FIG. 6B.
COMPARATIVE EXAMPLE 3
[0153] Reaction in Presence of Zinc (Zn) Catalyst Using Oxidant
(2g) at 80 .quadrature.
[0154] The reaction was carried out in the presence of
Zn(OTf).sub.2 as a zinc catalyst according to Reaction Scheme 14
below.
##STR00023##
[0155] The reaction was carried out according to Experimental
Procedure 1 except that 2-Cl-pyridine-N-oxide (2a) was replaced
with an oxidant (2g; 2 eq., 200 mol %) and 10 mol % of HNTf.sub.2
was substituted with 5 mol % of Zn(OTf).sub.2. The reaction was
carried out at 80 .quadrature. for 1 hour, and the separation by
chromatography gave a yield of 92%. Chiral HPLC analysis was
performed using the Chiralpak.RTM. IC column (66.2% ee). The
results are shown in FIG. 6C.
EXAMPLE 3
[0156] The reaction was carried out according to Reaction Scheme 15
below.
##STR00024##
[0157] The reaction was carried out according to Example 2 except
that 2.5 mol % of HNTf2 was used as an acid catalyst. As a result,
a high yield of about 92% was obtained, which indicates that the
product (3a) could be effectively synthesized on a gram-scale.
[0158] According to Comparative Examples 1 to 3, it can be seen
that the metal catalyst can also achieve the enantio-induction at a
significant level of about 66-82% ee. Referring to FIG. 3, the
metal-adduct (A.sub.metal) may pass through a stereogenic SN2'
addition (route A) after the conversion into A by
photo-demetallation. Alternatively, the S.sub.N2' route may occur
on A.sub.metal, and then the non-racemized photo-demetallation from
C- or O-linked enolate B1/B2 may occur (Route B).
EXAMPLE 4
[0159] Confirmation of Presence of Ynamide/N-Oxide Adduct
[0160] In the present example, it was examined whether the reaction
of an alkyne compound (ynamide) and a N--O bond oxidant in the
presence of an acid catalyst resulted in the formation of an
ynamide/N-oxide adduct. For this, the reaction was carried out
according to Reaction Scheme 16 below.
##STR00025##
[0161] An ynamide (1a) (0.1 mmol), HNTf.sub.2 (0.2 mmol), and
2-Cl-pyridine-N-oxide (0.2 mmol) were dissolved in DCE (0.2 mL),
and the mixture was reacted at room temperature for 10 hours,
followed by sampling. The presence or absence of the adduct was
examined using Q-TOF MS. The results are shown in FIG. 7A.
[0162] As shown in the drawing, the Q-TOF MS analysis results
confirmed the presence of an ynamide/N-oxide anion matched to the
.sup.35Cl/.sup.37Cl isotope pattern.
[0163] Subsequently, N-methyl indole (0.3 mmol) was added to the
mixture, followed by incubation at room temperature for 5 minutes,
followed by sampling and Q-TOF MS analysis. The results are shown
in FIG. 7B.
[0164] As shown in the drawing, the Q-TOF MS analysis results
confirmed that an ynamide/N-oxide anion and a product (3a) were
formed.
EXAMPLE 5
[0165] Evaluation of Rate-Determining Step
[0166] The deuteration incorporation experiment was conducted to
determine the rate-determining step in the oxygenative coupling
reaction according to the present disclosure.
[0167] The 3-deuteroated N-methyl indole was prepared as
follows:
[0168] N-Me-indole was dissolved in MeOH-d.sub.4 and the mixture
was treated with 5 mol % of HNTf.sub.2. The solvent was removed,
and the residue was partitioned between n-hexane and D.sub.2O. The
organic layer was separated and concentrated.
[0169] .sup.1H NMR spectra of N-Me-indole (CDCl.sub.3, t1=5 ms) and
3-d-N-Me-indole (98% D, CDCl3, t1=5 ms) are shown in FIGS. 8A and
8B. In order to accurately quantify the amount of protons, .sup.1H
NMR spectrum was obtained at T1 (spin-lattice relaxation time)=5
ms.
[0170] Referring to the drawing, as a result of the .sup.1H NMR
analysis in CDCl.sub.3, the complete deuterium exchange occurred,
and such a material did not contain HNTf.sub.2 as confirmed from
the absence of peaks in .sup.19F-NMR.
[0171] The proton exchange between C(3)-H of the N-Me-indole and
HNTf.sub.2 is rapid, and thus, the following composition was
prepared by carefully mixing 3H-N-Me-indole and 3-D-N-Me-indole
together with a catalytic amount of HNTf.sub.2 in 1,2-DCE: 300 mol
% of N-Me-indole (50% D) and 5 mol % of HNTf.sub.2 (50% D). The
isotopic composition of the mixture was measured by .sup.1H NMR,
and the results are shown in FIG. 8C (mixture of 3-H(D)-N-Me-indole
(300 mol %, 49% D) and H(D)NTf.sub.2 (5 mol %, 49% D)).
[0172] Thereafter, the reaction was carried out according to
Reaction Scheme 17 below.
##STR00026##
[0173] 100 mol % of an ynamide (1a) and 2-Cl-pyridine-N-oxide (2a)
were dissolved in 1,2-DCE, followed by treatment of the foregoing
solution at room temperature (anhydrides of the ynamide (1a) and
2-Cl-pyridine-N-oxide (2a) were prepared by azeotropic drying with
benzene prior to the reaction). After 1.5 hours at room
temperature, the crude .sup.1H NMR spectrum of the product (3a) was
obtained. FIG. 8D shows the .sup.1H NMR spectrum (CDCl 3, t 1=5 ms)
of the reference 3a-H and FIG. 8E shows the .sup.1H NMR spectrum
(CDCl 3, t 1=5 ms) of the 3a-H/D from the reaction product.
According to the drawing, the incorporation of deuterium into the
product (3a) was 25% D.
[0174] The deuterium content in the product (3a) was the same even
after chromatographic purification. Therefore, the kinetic isotope
effect was obtained by integrating vinyl peaks, and the
k.sub.H/k.sub.D ratio was 3.0 (75/25). Particularly, the
k.sub.H/k.sub.D ratio was evaluated to exceed 2.3 after the
calibration for the proton source from the HNTf.sub.2 catalyst.
[0175] Therefore, it could be confirmed that the rate-determining
step was the protonation of the ynamide or the deprotonation from
the initial indolyl .sigma.-complex.
EXAMPLE 6
[0176] Evaluation of Effect According to Reaction Condition
Change
[0177] In the present example, in the oxygenative coupling reaction
of an alkyne compound according to Reaction Scheme 18 below, the
effects according to reaction conditions (the concentration of the
alkyne compound in the reaction medium, the stoichiometric ratio of
the reactants, the amount of the acid catalyst used, and the
reaction temperature) were evaluated.
##STR00027##
[0178] A. Effect According to Concentration of Alkyne Compound in
Reaction Medium (Solvent)
[0179] The oxygenative coupling reaction.sup.a was carried out
while the concentration of the ynamide (molar concentration) in the
reaction medium was varied (a: reaction conditions: ynamide (0.1
mmol), N-oxide (0.2 mmol), 1-methyl indole (0.3 mmol), and an acid
catalyst (10 mol %) were reacted in DCE; and b: the yield was
measured by .sup.1H NMR spectrum using diethyl phthalate as a
self-reference, and the isolated yield are shown in the
parentheses). The results are shown in Table 3.
TABLE-US-00003 TABLE 3 Molar Reaction Entry concentration
conditions Yield (%).sup.b 1 0.025 RT, 21 h 46 2 0.050 RT, 10 h 51
3 0.10 RT, 7 h 59 4 0.20 RT, 4 h 70 (62) 5 0.50 RT, 2 h 73 (68) 6
0.70 RT, 2 h 73 7 0.80 RT, 2 h 67 8 1.00 RT, 2 h 63 9 neat RT, 2 h
54
[0180] B. Effect According to Stoichiometric Ratio of Reactants
[0181] The oxygenative coupling reaction.sup.a was carried out
while the stoichiometric ratio of reactants (ynamide, N-oxide
oxidant, and nucleophile) was varied (a: reaction conditions:
ynamide (0.1 mmol), N-oxide (0.2 mmol), 1-methyl indole (0.3 mmol),
and an acid catalyst (10 mol %) were reacted in DCE (0.5 M); and b:
the yield was measured by .sup.1H NMR spectrum using diethyl
phthalate as a self-reference). The results are shown in Table
4.
TABLE-US-00004 TABLE 4 Equivalent Reaction Entry Ynamide Oxidant
Nucleophile conditions Yield (%).sup.b 1 1.0 1.2 1.2 RT, 5 h 37 2
1.0 1.2 2.0 RT, 3 h 47 3 1.0 2.0 3.0 RT, 3 h 66 4 1.0 3.0 2.0 RT, 5
h 47 5 1.0 1.2 2.0 RT, 5 h 41 6 1.0 1.2 1.5 RT, 5 h 36 7 1.0 2.0
1.2 RT, 8 h 41 8 1.0 2.0 2.0 RT, 2 h. 60
[0182] C. Effect According to Amount of acid Catalyst Used
[0183] The oxygenative coupling reaction.sup.a was carried out
while the amount of acid catalyst used was varied (a: reaction
conditions: ynamide (0.1 mmol), N-oxide (0.2 mmol), 1-methyl indole
(0.3 mmol), and an acid catalyst were reacted in DCE (0.5 M); and
b: the yield was measured by .sup.1H NMR spectrum using diethyl
phthalate as a self-reference). The results are shown in Table
5.
TABLE-US-00005 TABLE 5 Amount of Reaction Entry acid used
conditions Yield (%).sup.b 1 1 mol % RT, 4 days 30 2 5 mol % RT, 15
h 41 3 10 mol % RT, 6 h 58 4 20 mol % RT, 2 h 69 5 30 mol % RT, 2 h
71
[0184] D. Effect According to Reaction Temperature
[0185] The oxygenative coupling reaction.sup.a was carried out
while the reaction temperature was varied (a: reaction conditions:
ynamide (0.1 mmol), N-oxide (0.2 mmol), 1-methyl indole (0.3 mmol),
and an acid catalyst (10 mol %) were reacted in DCE (0.5 M); and b:
the yield was measured by .sup.1H NMR spectrum using diethyl
phthalate as a self-reference). The results are shown in Table
6.
TABLE-US-00006 TABLE 6 Reaction Entry temperature Time Yield
(%).sup.b 1 RT 3.5 h 65 2 50.degree. C. 1.0 h 60 3 80.degree. C.
1.0 h 55
[0186] Accordingly, simple modifications, additions and
substitutions of the present invention should also be understood as
falling within the scope of the present invention, without
departing from the scope and spirit of the invention as disclosed
in the accompanying claims.
* * * * *